Pyroglutamylated amyloid-[beta] is associated with hyperphosphorylated tau and severity of Alzheimer's disease

Pyroglutamylated amyloid-[beta] (pE(3)-A[beta]) has been suggested to play a major role in Alzheimer's disease (AD) pathogenesis as amyloid-[beta] (A[beta]) oligomers containing pE(3)-A[beta] might initiate tau-dependent cytotoxicity. We aimed to further elucidate the associations among pE(3)-A[beta], full-length A[beta] and hyperphosphorylated tau (HP-[tau]) in human brain tissue. We examined 41 post mortem brains of both AD (n = 18) and controls. Sections from frontal and entorhinal cortices were stained with pE(3)-A[beta], HP-[tau] and full-length A[beta] antibodies. The respective loads were assessed using image analysis and western blot analysis was performed in a subset of cases. All loads were significantly higher in AD, but when using A[beta] loads as independent variables only frontal pE(3)-A[beta] load predicted AD. In frontal and entorhinal cortices pE(3)-A[beta] load independently predicted HP-[tau] load while non-pE(3)-A[beta] failed to do so. All loads correlated with the severity of AD neuropathology. However, partial correlation analysis revealed respective correlations in the frontal cortex only for pE(3)-A[beta] load only while in the entorhinal cortex respective correlations were seen for both HP-[tau] and non-pE(3)-A[beta] loads. Mini Mental State Examination scores were independently predicted by entorhinal HP-[tau] load and by frontal pE(3)-A[beta] load. Here, we report an association between pE(3)-A[beta] and HP-[tau] in human brain tissue and an influence of frontal pE(3)-A[beta] on both the severity of AD neuropathology and clinical dementia. Our findings further support the notion that pE(3)-A[beta] may represent an important link between A[beta] and HP-[tau], and investigations into its role as diagnostic and therapeutic target in AD are warranted.[PUBLICATION ABSTRACT]